A critical step in the development of a solid tumor is the transition of a dormant or slowly growing avascular tumor into a rapidly growing metastatic vascularized tumor. This process of neovascularization depends on the ability of capillary endothelial cells to complete the processes of hydrolysis of basement membrane around pre-existing vessels, migration toward the tumor stimulus, cell proliferation, and the formation of closed vascular channels. We have succeeded in culturing capillary endothelial cells and have used them to develop in vitro assays for the cellular components of the vascular process. The isolation and identification of these cells have been greatly aided by the use of fluorescently labeled acetyl low-density lipoprotein which is selectively taken up by endothelial cells and macrophages. After internalization of this probe, the endothelial cells can be selected and isolated by use of a fluorescence-activated cell sorter. In vitro assays employing capillary endothelial cells have been of use in the identification and isolation of tumor-derived stimulators of neovascularization, and they have also been used for the detection of such factors in biological fluids from tumor-bearing individuals. In the next phase of this project, we will attempt to more fully understand the factors that control growth, migration, and adhesion of capillary endothelial cells by utilizing assays that can distinguish the directional, nondirectional, and adhesive components of endothelial cell motility. We also plan to explore the complex interactions between capillary endothelial cells and other motile cells such as mast cells and eosinophils that may release factors that modulate the rate and direction of new capillary growth. (J)
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